Endocrine Metabolism IV: Thyroid Gland
A deficiency of thyroid hormone during fetal develop-
ment due to untreated or undertreated maternal hypothy-
roidism results in a neurological deficit in the offspring. In
congenital hypothyroidism, a normal maternal thyroid can
meet the fetal requirements for thyroid hormone. However,
in the postnatal period these infants require a prompt thy-
roid hormone replacement therapy throughout their life,
beginning in the first few weeks of life. If untreated, they
inevitably develop growth and mental retardation. Thy-
roid hormone is essential for maturational development of
the CNS and is required for the development of axonal
projections and myelination. One of the important effects
of thyroid hormone is to promote the synthesis of myelin
basic protein.
Congenital hypothyroidism
in Western populations
occurs in about 1 in 4000 births. Congenital hypothy-
roidism is caused by embryogenic defects leading to
thyroid agenesis (50-55%), dysgenesis (30-35%), errors
in the synthesis of thyroid hormone (10-15%), and defects
in the pituitary-hypothalamic axis (4%). Neonatal screen-
ing for congenital hypothyroidism is performed using
blood collected on filter paper from newborns older than
12 hours. The laboratory test consists of measuring T4,
TSH, or both. Abnormal values must be reconfirmed and
additional tests include other parameters (e.g., TBG).
Reproductive System
Thyroid hormone increases total plasma androgen lev-
els by increasing the production of testosterone-binding
globulin (TeBG) by the liver. Hyperthyroidism is asso-
ciated with increased plasma TeBG levels, higher total
testosterone levels, but normal free testosterone levels in
adult men. There is a high incidence of gynecomastia in hy-
perthyroid men (40-83%) due to a higher circulating level
of free estradiol in plasma. The elevated free-estradiol
level may be explained by the lower affinity of estrogen
for TeBG and also by increased conversion of androgen to
estrogen in hyperthyroidism.
In prepubertal boys, but not in older boys or adult
men, hypothyroidism is associated with a high incidence
of increased testicular growth (macroorchidism) that is
not accompanied by any change in testosterone levels.
Elevated follicle-stimulating hormone levels are found in
most cases, but there is no testicular maturation. The mech-
anism of this disorder is not known.
Pharmacological Effects
The effects of thyroid hormone may persist for up to a
week because of its long half-life in the circulation, its
long-acting effect on the genome of the target cell, and the
slow rate of recovery of some target tissues (e.g., brain).
Thyroid hormone excess depletes body energy stores
and imparts hypersensitivity of tissues to catecholamines.
Protein synthesis is inhibited, protein catabolism is ac-
celerated, and the antianabolic actions of cortisol are en-
hanced. During the period of growth, these factors would
lead to growth suppression, muscle weakness, weight
loss, and depletion of liver and muscle glycogen stores.
Gluconeogenesis is fueled by elevated substrate levels
(amino acids, glycerol, lactate, and pyruvate), and this
contributes to the blood glucose pool; however, since
peripheral glucose utilization is also increased, hyper-
glycemia is not severe. Thyroid excess also leads to de-
pletion of triacylglycerol stores, mainly due to its action
on catecholamine-induced lipolysis. Tissue consumption
of free fatty acids and ketones is also increased. Thus,
serum lipid levels fall, including the level of serum choles-
terol. In essence, the storage forms of glucose, amino
acids, and fatty acids are depleted, and these substrates
are rapidly metabolized, resulting in the need for increased
food intake.
Because thyroid hormone increases tissue respon-
siveness to catecholamines, many symptoms of thyroid
hormone excess are those that characterize catecholamine
excess. Effects of T
on cardiovascular hemodynam-
ics consist of increased tissue thermogenesis, decreased
systemic vascular resistance, decreased effective arterial
filling volume, increased renal sodium reabsorption, in-
creased blood volume, increased cardiac inotropy and
chronotropy leading to increased cardiac output. Behav-
ioral changes (such as nervousness, restlessness, short at-
tention span, and emotional lability) are common, some
of which require a longer period for decay than do the
metabolic changes following normalization of thyroid
hormone levels. Clearly, the central actions of thyroid hor-
mone involve more than potentiation of adrenergic neuro-
Thyroid disorders.
Disturbances in thyroid metabolism
can occur at any level of the hypothalams-pituitary-
thyroid-peripheral tissue axis. Several of these disorders
have been discussed previously. Hyperthyroidism is more
prevalent in women than men. The three most common
causes of hyperthyroidism are Graves’ hyperthyroidism,
toxic multinodular goiter, and toxic adenoma. The clinical
features of hyperthyroidism include hyperkinesis, weight
loss, cardiac anomalies (e.g., atrial fibrillation), fatigue,
weakness, sweating, palpitations, and nervousness. The
typical biochemical laboratory parameters are increased
serum free T
and decreased serum TSH.
The most common cause of hypothyroidism is failure
of the thyroid gland; this is known as primary hypothy-
roidism. In adults, the cause of primary hypothyroidism is
often spontaneous autoimmune disease (e.g., Hashimoto’s
thyroiditis) or destructive therapy for hyperthyroid states
previous page 810 Bhagavan Medical Biochemistry 2001 read online next page 812 Bhagavan Medical Biochemistry 2001 read online Home Toggle text on/off